N-Acylethanolamines (NAEs) are potent, bioactive lipid signaling substances with diverse roles in mammalian physiology. We propose to investigate plant-derived NAEs functioning both as potential alternatives and supplements to currently existing neuroprotecting treatments for neurological disorders including Alzheimer's disease. Our preliminary data indicate that NAEs regulate the function of intracellular calcium channels allowing modulation of intracellular calcium signaling. NAEs are naturally occurring compounds, and therefore there are in place metabolic and clearance processes for these compounds lessening the likelihood of NAE-associated toxicities. The central hypothesis of this application is that NAEs exert protective effects on neurons. The mechanisms of neuroprotection mediated by NAEs will be analyzed and evaluated at the molecular level, in neuronal cell lines, primary neuronal cultures and in vivo as models of neurotoxic insults and neurodegeneration. In particular, the effect of NAEs will be evaluated for their ability to prevent cell death and elicit neuroprotection-related signaling pathways. The specific aims are: 1) Analyze the modulation of biophysical and pharmacological characteristics of intracellular calcium channels by NAEs; 2) to identify and measure the contribution of NAE mediated responses to intracellular Ca 2+ signaling of neurons; 3) to determine the neuroprotective effects of NAEs in neuronal cell lines as models of neurotoxic insults and neurodegeneration; 4) to identify the neuroprotective signal transduction pathways elicited by NAEs in primary neuronal cultures of the hippocampus as models of neurotoxic insults and neurodegeneration.; 5) to determine the effects of NAEs on ischemic damage in an animal model of stroke. Experiments will use a combination of biochemistry, electrophysiology, optical imaging of intracellular Ca 2+ concentrations, analyses of changes in intracellular signaling and neuroprotection assays. The overall goal of this study is to provide the necessary foundation for the development of novel alternative or supplemental treatments for neurodegeneration in Alzheimer's disease.